Inborn errors of immunity manifesting as atopic disorders

Vaseghi‐Shanjani, Maryam; Smith, Kelsey L.; Sara, Rahnuma; Modi, Bhavi P.; Branch, Anna; Sharma, Mehul; Lu, Henry Y.; James, E; Hildebrand, Kyla J.; Biggs, Catherine M.; Turvey, Stuart E.

doi:10.1016/j.jaci.2021.08.008

Cited by 29 publications

(31 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…AD is a complex disease whose etiology has not yet been fully deciphered due to its heterogeneity resulting from patient age, ethnicity, and lifestyle factors [7][8][9]. Moreover, although a genetic predisposition is undeniable in AD pathogenesis, the relative contribution of (epi)genetic [10][11][12][13] versus environmental factors [14][15][16] remains unknown. Heterogeneity of AD due to genetic polymorphism extends beyond filaggrin (FLG) loss-of-function mutations, since patients with serine peptidase inhibitor Kazal-type 5 (SPINK5) mutations also exhibit a severe AD-like phenotype, as do other patients with inherited disorders [17,18].…”

Section: Atopic Dermatitismentioning

confidence: 99%

“…While it is clear that AD is a consequence of impaired epidermal barrier function associated with immune hyper-responsiveness, probably resulting from (epi)genetic modifications [10,11,13], it is not clear which abnormality-stratum corneum (SC) versus immune pathology-occurs first. The widely cited work from Kelleher et al which purportedly showed increased transepidermal water loss (TEWL) in 2-day-old children preceding the development of AD and allergies later on [48] has been recently retracted [49].…”

Section: Pathogenesis Of Atopic Dermatitismentioning

confidence: 99%

See 1 more Smart Citation

Atopic Dermatitis: The Fate of the Fat

Pavel

Blunder

Moosbrugger‐Martinz

et al. 2022

IJMS

View full text Add to dashboard Cite

Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease in which dry and itchy skin may develop into skin lesions. AD has a strong genetic component, as children from parents with AD have a twofold increased chance of developing the disease. Genetic risk loci and epigenetic modifications reported in AD mainly locate to genes involved in the immune response and epidermal barrier function. However, AD pathogenesis cannot be fully explained by (epi)genetic factors since environmental triggers such as stress, pollution, microbiota, climate, and allergens also play a crucial role. Alterations of the epidermal barrier in AD, observed at all stages of the disease and which precede the development of overt skin inflammation, manifest as: dry skin; epidermal ultrastructural abnormalities, notably anomalies of the lamellar body cargo system; and abnormal epidermal lipid composition, including shorter fatty acid moieties in several lipid classes, such as ceramides and free fatty acids. Thus, a compelling question is whether AD is primarily a lipid disorder evolving into a chronic inflammatory disease due to genetic susceptibility loci in immunogenic genes. In this review, we focus on lipid abnormalities observed in the epidermis and blood of AD patients and evaluate their primary role in eliciting an inflammatory response.

show abstract

Section: Atopic Dermatitismentioning

confidence: 99%

Section: Pathogenesis Of Atopic Dermatitismentioning

confidence: 99%

Atopic Dermatitis: The Fate of the Fat

Pavel

Blunder

Moosbrugger‐Martinz

et al. 2022

IJMS

View full text Add to dashboard Cite

show abstract

“…Furthermore, defects in the genes encoding upstream and downstream proteins in the STAT pathway (e.g. ZNF341, DOCK8, IL6ST, IL6R, and ERBIN) also result in severe allergic diseases 26 . The recent increased recognition of PADs is valuable because: (i) the identification of affected pathways provide important insights into the pathogenesis of allergic inflammation and may uncover new treatment targets; (ii) these conditions are likely under-diagnosed since allergies are traditionally believed to be complex polygenic disorders; and (iii) diagnosis of PADs can be transformative for affected individuals and their families by guiding treatment options, and informing relevant considerations tied to genetic counselling including family planning, long term prognosis, and connection to other families with the same genetic disease.…”

Section: Introductionmentioning

confidence: 99%

“…In 2018, the term primary atopic disorders (PADs) was coined to describe heritable genetic disorders presenting with dysregulated pathogenic allergic effector responses [24][25][26] . PADs are a subgroup of inborn errors of immunity (IEIs) that manifest with prominent allergic inflammation, in the presence or absence of other clinical features associated with IEIs, such as enhanced susceptibility to infections, autoimmunity, and malignancy.…”

Section: Introductionmentioning

confidence: 99%

Human Germline Heterozygous Gain-of-Function STAT6 Variants Cause Severe Allergic Disease

Sharma

Vaseghi‐Shanjani

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

STAT6 (Signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. STAT6 mediates the biological effects of IL-4, a cytokine necessary for type 2 differentiation of T cells and B cell survival, proliferation and class switching to IgE. We have identificated two unrelated patients with a phenotype notable for their early-life onset of profound allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic esophagitis, elevated serum IgE, IgE-mediated food allergies, and vascular anomalies of the brain. Both patients harbored heterozygous de novo missense variants in the DNA binding domain of STAT6 (c.1144G>C, p.E382Q; and c.1256A>G, p.D419G). Functional studies established that both variants caused a gain-of-function (GOF) phenotype associated with enhanced phosphorylation and transcriptional activity of STAT6, in addition to increased transcript abundance of known STAT6 target genes and other genes implicated in allergic disease. JAK inhibitors decreased the enhanced STAT6 responses associated with both these STAT6 GOF variants. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of the first humans with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder.

show abstract

“…PADs may be particularly difficult to identify owing to the high prevalence of polygenic allergic disease (28)(29)(30). Clinical red flags for PADs that have been suggested in the literature include severe atopy, autoimmunity, malignancy, connective tissue disease, growth failure/short stature, and recurrent infections (31,32). In this study we looked for laboratory evidence of type 2 inflammation in the USIDNET registry and found that approximately one in five patients with an IEI attributable to a monogenic defect had eosinophilia and/or an elevated IgE level.…”

Section: Discussionmentioning

confidence: 99%

Inborn Errors of Immunity Associated With Type 2 Inflammation in the USIDNET Registry

et al. 2022

Self Cite

View full text Add to dashboard Cite

BackgroundMonogenic conditions that disrupt proper development and/or function of the immune system are termed inborn errors of immunity (IEIs), also known as primary immunodeficiencies. Patients with IEIs often suffer from other manifestations in addition to infection, and allergic inflammation is an increasingly recognized feature of these conditions.MethodsWe performed a retrospective analysis of IEIs presenting with allergic inflammation as reported in the USIDNET registry. Our inclusion criteria comprised of patients with a reported monogenic cause for IEI where reported lab eosinophil and/or IgE values were available for the patient prior to them receiving potentially curative therapy. Patients were excluded if we were unable to determine the defective gene underlying their IEI. Patients were classified as having eosinophilia or elevated IgE when their record included at least 1 eosinophil count or IgE value that was greater than the age stratified upper limit of normal. We compared the proportion of patients with eosinophilia or elevated IgE with the proportion of samples in a reference population that fall above the upper limit of normal (2.5%).ResultsThe query submitted to the USIDNET registry identified 1409 patients meeting inclusion criteria with a monogenic cause for their IEI diagnosis, of which 975 had eosinophil counts and 645 had IgE levels obtained prior to transplantation or gene therapy that were available for analysis. Overall, 18.8% (183/975) of the patients evaluated from the USIDNET registry had eosinophilia and 20.9% (135/645) had an elevated IgE. IEIs caused by defects in 32 genes were found to be significantly associated with eosinophilia and/or an elevated IgE level, spanning 7 of the 10 IEI categories according to the International Union of Immunological Societies classification.ConclusionType 2 inflammation manifesting as eosinophilia or elevated IgE is found in a broad range of IEIs in the USIDNET registry. Our findings suggest that allergic immune dysregulation may be more widespread in IEIs than previously reported.

show abstract

Inborn errors of immunity manifesting as atopic disorders

Cited by 29 publications

References 76 publications

Atopic Dermatitis: The Fate of the Fat

Atopic Dermatitis: The Fate of the Fat

Human Germline Heterozygous Gain-of-Function STAT6 Variants Cause Severe Allergic Disease

Inborn Errors of Immunity Associated With Type 2 Inflammation in the USIDNET Registry

Contact Info

Product

Resources

About